DUSP3 maintains genomic stability and cell proliferation through modulation of the NER pathway and cell cycle regulatory proteins

Author(s)

Russo, Lilian Cristina ^[1] ; Farias, Jessica Oliveira ^[1] ; Forti, Fabio Luis ^[1]

Affiliation

^[1] Univ Sao Paulo, Inst Chem, Dept Biochem, Lab Signaling Biomol Syst, Sao Paulo, SP - Brazil

• Document type: Journal article
• Source: CELL CYCLE; v. 19, n. 12 MAY 2020.
• Web of Science Citations: 0

Abstract

The DUSP3 phosphatase regulates cell cycle, proliferation, apoptosis and senescence of different cell types, lately shown as a mediator of DNA repair processes. This work evaluated the impact of DUSP3 loss of function (lof) on DNA repair-proficient fibroblasts (MRC-5), NER-deficient cell lines (XPA and XPC) and translesion DNA synthesis (TLS)-deficient cells (XPV), after UV-radiation stress. The levels of DNA strand breaks, CPDs and 6-4-PPs have accumulated over time in all cells under DUSP3 lof, with a significant increase in NER-deficient lines. The inefficient repair of these lesions increased sub-G1 population of XPA and XPC cells 24 hours after UV treatment, notably marked by DUSP3 lof, which is associated with a reduced cell population in G1, S and G2/M phases. It was also detected an increase in S and G2/M populations of XPV and MRC-5 cells after UV-radiation exposure, which was slightly attenuated by DUSP3 lof due to a discrete increase in sub-G1 cells. The cell cycle progression was accompanied by changes in the levels of the main Cyclins (A1, B1, D1 or E1), CDKs (1, 2, 4 or 6), and the p21 (Cip1) inhibitor, in a DUSP3-dependent manner. DUSP3 lof affected the proliferation of MRC-5 and XPA cells, with marked worsening of the XP phenotype after UV radiation. This work highlights the roles of DUSP3 in DNA repair fitness and in the fine control of regulatory proteins of cell cycle, essential mechanisms to maintenance of genomic stability. (AU)

• FAPESP's process: 17/16491-4 - Evaluation of VHR and NPM proteins in DNA repair and proliferation of leukemic cells
• Grantee: Jessica Oliveira Farias
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 15/03983-0 - Molecular and functional investigation of the interactions between DUSP3 with nuclear proteins and its implications in DNA repair mechanisms
• Grantee: Fábio Luis Forti
• Support Opportunities: Regular Research Grants
• FAPESP's process: 18/01753-6 - Identification and functional investigation of proteins that interact with Cdc42 and DUSP12 enzymes in human cells under conditions of genomic instability: a proteomic approach
• Grantee: Fábio Luis Forti
• Support Opportunities: Regular Research Grants